The present invention relates to pharmaceutical agents (compounds) which are useful as xcex1vxcex23 integrin antagonists or inhibitors and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by xcex1vxcex23 by inhibiting or antagonizing xcex1vxcex23 integrins.
Integrins are a group of cell surface glycoproteins which mediate cell adhesion and therefore are useful mediators of cell adhesion interactions which occur during various biological processes. Integrins are heterodimers composed of noncovalently linked xcex1 and xcex2 polypeptide subunits. Currently eleven different xcex1 subunits have been identified and six different xcex2 subunits have been identified. The various xcex1 subunits can combine with various xcex2 subunits to form distinct integrins.
The integrin identified as xcex1vxcex23 (also known as the vitronectin receptor) has been identified as an integrin which plays a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis, Paget""s disease, humoral hypercalcemia of malignancy, angiogenesis, including tumor angiogenesis, retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis). Additionally, it has been found that such agents would be useful as antivirals, antifungals and antimicrobials. Thus, compounds which selectively inhibit or antagonize xcex1vxcex23 would be beneficial for treating such conditions.
It has been shown that the xcex1vxcex23 integrin and other xcex1v containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules. Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors. However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides which bind to xcex1vxcex23 also bind to xcex1vxcex25, xcex1vxcex21 and xcex1IIbxcex23. Antagonism of platelet xcex1IIbxcex23 (also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions or disease states associated with the integrin xcex1vxcex23, it would be beneficial to develop compounds which are selective antagonists of xcex1vxcex23 as opposed to xcex1IIbxcex23.
Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor.
Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561) have shown that the xcex1vxcex23 integrin has a biological function in melanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that the integrin xcex1vxcex23 expressed on human melanoma cells promotes a survival signal, protecting the cells from apoptosis. Mediation of the tumor cell metastatic pathway by interference with the xcex1vxcex23 integrin cell adhesion receptor to impede tumor metastasis would be beneficial.
Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstrated that antagonists of xcex1vxcex23 provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) since systemic administration of xcex1vxcex23 antagonists causes dramatic regression of various histologically distinct human tumors.
The adhesion receptor integrin xcex1vxcex23 was identified as a marker of angiogenic blood vessels in chick and man and therefore such receptor plays a critical role in angiogenesis or neovascularization. Angiogenesis is characterized by the invasion, migration and proliferation of smooth muscle and endothelial cells. Antagonists of xcex1vxcex23 inhibit this process by selectively promoting apoptosis of cells in neovasculature. The growth of new blood vessels, or angiogenesis, also contributes to pathological conditions such as diabetic retinopathy (Adonis et al., Amer. J. Ophthal., Vol. 118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med., Vol. 175, (1992), 1135-1138). Therefore, xcex1vxcex23 antagonists would be useful therapeutic targets for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571).
It has been reported that the cell surface receptor xcex1vxcex23 is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption and when such bone resorbing activity exceeds bone forming activity it results in osteoporosis (a loss of bone), which leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of xcex1vxcex23 have been shown to be potent inhibitors of osteoclastic activity both in vitro [Sato et al., J. Cell. Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al., Endocrinology, Vol. 132 (1993) 1411-1413]. Antagonism of xcex1vxcex23 leads to decreased bone resorption and therefore restores a normal balance of bone forming and resorbing activity. Thus it would be beneficial to provide antagonists of osteoclast xcex1vxcex23 which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis.
The role of the xcex1vxcex23 integrin in smooth muscle cell migration also makes it a therapeutic target for prevention or inhibition of neointimal hyperplasia which is a leading cause of restenosis after vascular procedures (Choi et al., J. Vasc. Surg. Vol. 19(1) (1994) 125-34). Prevention or inhibition of neointimal hyperplasia by pharmaceutical agents to prevent or inhibit restenosis would be beneficial.
White (Current Biology, Vol. 3(9)(1993) 596-599) has reported that adenovirus uses xcex1vxcex23 for entering host cells. The integrin appears to be required for endocytosis of the virus particle and may be required for penetration of the viral genome into the host cell cytoplasm. Thus compounds which inhibit xcex1vxcex23 would find usefulness as antiviral agents.
The present invention relates to a class of compounds represented by the Formula I 
or a pharmaceutically acceptable salt thereof, wherein
B is selected from the group consisting of xe2x80x94CONR50xe2x80x94 and xe2x80x94SO2NR50xe2x80x94;
A is 
wherein Y1 is selected from the group consisting of Nxe2x80x94R2, O, and S;
R2 is selected from the group consisting of H; alkyl; aryl; hydroxy; alkoxy; cyano; nitro; amino; alkenyl; alkynyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles; aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycle; monocyclic heterocycles; and monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl; or
R2 taken together with R7 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy and phenyl;
or R2 taken together with R7 forms a 5 membered heteroaromatic ring;
or R2 taken together with R7 forms a 5 membered heteroaromatic ring fused with a phenyl group;
R7 when not taken together with R2) and R8 are independently selected from the group consisting of H; alkyl; alkenyl; alkynyl; aralkyl; cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl; alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, fused monocyclic heterocycles; aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles; monocyclic heterocycles; monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl; monocyclic and bicyclic heterocyclicalkyls; xe2x80x94SO2R10 wherein R10 is selected from the group consisting of alkyl, aryl and monocyclic heterocycles, all optionally substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclic heterocycles; and 
wherein R10 is defined above;
or NR7 and R8 taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S;
R5 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, benzyl, and phenethyl;
or
A is 
wherein Y2 is selected from the group consisting of H, alkyl; cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles; alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl; aryl optionally substituted with one or more substituent selected from halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl; alkynyl; alkenyl; xe2x80x94Sxe2x80x94R9 and xe2x80x94Oxe2x80x94R9 wherein R9 is selected from the group consisting of H; alkyl; aralkyl; aryl; alkenyl; and alkynyl; or R9 taken together with R7 forms a 4-12 membered mononitrogen containing sulfur or oxygen containing heterocyclic ring; and
R5 and R7 are as defined above;
or Y2 (when Y2 is carbon) taken together with R7 forms a 4-12 membered mononitrogen containing ring optionally substituted with alkyl, aryl or hydroxy;
Z1, Z2, Z4 and Z5 are independently selected from the group consisting of H; alkyl; hydroxy; alkoxy; aryloxy; aralkoxy; halogen; haloalkyl; haloalkoxy; nitro; amino; aminoalkyl; alkylamino; dialkylamino; cyano; alkylthio; alkylsulfonyl; carboxyl derivatives; acetamide; aryl; fused aryl; cycloalkyl; thio; monocyclic heterocycles; fused monocyclic heterocycles; and A, wherein A is defined above;
R50 is selected from the group consisting of H and alkyl;
R1 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and aryl, optionally substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, hydroxy, alkoxy, aryloxy, aralkoxy, amino, aminoalkyl, carboxyl derivatives, cyano and nitro;
t is an integer 0, 1 or 2;
R is Xxe2x80x94R3 wherein X is selected from the group consisting of O, S and NR4, wherein R3 and R4 are independently selected from the group consisting of hydrogen; alkyl; alkenyl; alkynyl; haloalkyl; aryl; arylalkyl; sugars; steroids and in the case of the free acid, all pharmaceutically acceptable salts thereof; and
Y3 and Z3 are independently selected from the group consisting of H, alkyl, aryl, cycloalkyl and aralkyl.
It is another object of the invention to provide pharmaceutical compositions comprising compounds of the Formula I. Such compounds and compositions are useful in selectively inhibiting or antagonizing the xcex1vxcex23 integrin and therefore in another embodiment the present invention relates to a method of selectively inhibiting or antagonizing the xcex1vxcex23 integrin. The invention further involves treating or inhibiting pathological conditions associated therewith such as osteoporosis, humoral hypercalcemia of malignancy, Paget""s disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including diabetic retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis in a mammal in need of such treatment. Additionally, such pharmaceutical agents are useful as antiviral agents, and antimicrobials.
The present invention relates to a class of compounds represented by the Formula I, described above.
A preferred embodiment of the present invention is a compound of the Formula II 
Another preferred embodiment of the present invention is a compound of the Formula III 
The invention further relates to pharmaceutical compositions containing therapeutically effective amounts of the compounds of Formulas I-III.
The invention also relates to a method of selectively inhibiting or antagonizing the xcex1vxcex23 integrin and more specifically relates to a method of inhibiting bone resorption, periodontal disease, osteoporosis, humoral hypercalcemia of malignancy, Paget""s disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including diabetic retinopathy, arthritis, including rheumatoid arthritis, smooth muscle cell migration and restenosis by administering a therapeutically effective amount of a compound of the Formula I-III to achieve such inhibition together with a pharmaceutically acceptable carrier.
The following is a list of definitions of various terms used herein:
As used herein, the terms xe2x80x9calkylxe2x80x9d or xe2x80x9clower alkylxe2x80x9d refer to a straight chain or branched chain hydrocarbon radicals having from about 1 to about 10 carbon atoms, and more preferably 1 to about 6 carbon atoms. Examples of such alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl, and the like.
As used herein the terms xe2x80x9calkenylxe2x80x9d or xe2x80x9clower alkenylxe2x80x9d refer to unsaturated acyclic hydrocarbon radicals containing at least one double bond and 2 to about 6 carbon atoms, which carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety, relative to groups substituted on the double bond carbons. Examples of such groups are ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like.
As used herein the terms xe2x80x9calkynylxe2x80x9d or xe2x80x9clower alkynylxe2x80x9d refer to acyclic hydrocarbon radicals containing one or more triple bonds and 2 to about 6 carbon atoms. Examples of such groups are ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein means saturated or partially unsaturated cyclic carbon radicals containing 3 to about 8 carbon atoms and more preferably 4 to about 6 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-1-yl, and the like.
The term xe2x80x9carylxe2x80x9d as used herein denotes aromatic ring systems composed of one or more aromatic rings. Preferred aryl groups are those consisting of one, two or three aromatic rings. The term embraces aromatic radicals such as phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl and the like.
As used herein, the term xe2x80x9ccyanoxe2x80x9d is represented by a radical of the formula 
The terms xe2x80x9chydroxyxe2x80x9d and xe2x80x9chydroxylxe2x80x9d as used herein are synonymous and are represented by a radical of the formula 
The term xe2x80x9clower alkylenexe2x80x9d or xe2x80x9calkylenexe2x80x9d as used herein refers to divalent linear or branched saturated hydrocarbon radicals of 1 to about 6 carbon atoms.
As used herein the term xe2x80x9calkynylenexe2x80x9d or xe2x80x9clower alkynylenexe2x80x9d refers to an alkylene radical wherein at least one bond between the carbon atoms is unsaturated and such unsaturation forms a triple bond.
As used herein the term xe2x80x9calkenylenexe2x80x9d or xe2x80x9clower alkenylenexe2x80x9d refers to an alkylene radical wherein at least one bond between the carbon atoms is unsaturated and such unsaturation produces a double bond in cis or transconformation.
As used herein the term xe2x80x9calkoxyxe2x80x9d refers to straight or branched chain oxy containing radicals of the formula xe2x80x94OR20, wherein R20 is an alkyl group as defined above. Examples of alkoxy groups encompassed include methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, sec-butoxy, t-butoxy and the like.
As used herein the terms xe2x80x9carylalkylxe2x80x9d or xe2x80x9caralkylxe2x80x9d refer to a radical of the formula 
wherein R21 is aryl as defined above and R22 is an alkylene as defined above. Examples of aralkyl groups include benzyl, pyridylmethyl, naphthylpropyl, phenethyl and the like.
As used herein the term xe2x80x9caralkoxyxe2x80x9d or xe2x80x9carylakoxyxe2x80x9d refers to a radical of the formula 
wherein R53 is aralkyl as defined above.
As used herein the term xe2x80x9cnitroxe2x80x9d is represented by a radical of the formula 
As used herein the term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to bromo, chloro, fluoro or iodo.
As used herein the term xe2x80x9chaloalkylxe2x80x9d refers to alkyl groups as defined above substituted with one or more of the same or different halo groups at one or more carbon atom. Examples of haloalkyl groups include trifluoromethyl, dichloroethyl, fluoropropyl and the like.
As used herein the term xe2x80x9ccarboxylxe2x80x9d or xe2x80x9ccarboxyxe2x80x9d refers to a radical of the formula xe2x80x94COOH.
As used herein the term aminoalkylxe2x80x9d refers to a radical of the formula xe2x80x94R54xe2x80x94NH2 wherein R54 is lower alkylene as defined above.
As used herein the term xe2x80x9ccarboxyl derivativexe2x80x9d refers to a radical of the formula 
wherein Y6 and Y7 are independently selected from the group consisting of O, N or S and R23 is selected from the group consisting of H, alkyl, aralkyl or aryl as defined above.
As used herein the term xe2x80x9caminoxe2x80x9d is represented by a radical of the formula xe2x80x94NH2.
As used herein the term xe2x80x9calkylsulfonylxe2x80x9d or xe2x80x9calkylsulfonexe2x80x9d refers to a radical of the formula 
wherein R24 is alkyl as defined above.
As used herein the term xe2x80x9calkylthioxe2x80x9d refers to a radical of the formula xe2x80x94SR24 wherein R24 is alkyl as defined above.
As used herein the term xe2x80x9csulfonic acidxe2x80x9d refers to a radical of the formula 
wherein R25 is H, alkyl or aryl as defined above.
As used herein the term xe2x80x9csulfonamidexe2x80x9d refers to a radical of the formula 
wherein R7 and R8 are as defined above.
As used herein the term xe2x80x9cfused arylxe2x80x9d refers to an aromatic ring such as the aryl groups defined above fused to one or more phenyl rings. Embraced by the term xe2x80x9cfused arylxe2x80x9d is the radical naphthyl.
As used herein the terms xe2x80x9cmonocyclic heterocyclexe2x80x9d or xe2x80x9cmonocyclic heterocyclicxe2x80x9d refer to a monocyclic ring containing from 4 to about 12 atoms, and more preferably from 5 to about 10 atoms, wherein 1 to 3 of the atoms are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur with the understanding that if two or more different heteroatoms are present at least one of the heteroatoms must be nitrogen. Representative of such monocyclic heterocycles are imidazole, furan, pyridine, oxazole, pyran, triazole, thiophene, pyrazole, thiazole, thiadiazole, and the like.
As used herein the term xe2x80x9cfused monocyclic heterocyclexe2x80x9d refers to a monocyclic heterocycle as defined above with a benzene fused thereto. Examples of such fused monocyclic heterocycles include benzofuran, benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazole and the like.
As used herein the term xe2x80x9cmethylenedioxyxe2x80x9d refers to the radical 
and the term xe2x80x9cethylenedioxyxe2x80x9d refers to the radical 
As used herein the term xe2x80x9c4-12 membered dinitrogen containing heterocycle refers to a radical of the formula 
wherein m is 1 or 2 and R19 is H, alkyl, aryl, or aralkyl and more preferably refers to 4-9 membered ring and includes rings such as imidazoline.
As used herein the term xe2x80x9c5-membered heteroaromatic ringxe2x80x9d includes for example a radical of the formula 
and xe2x80x9c5-membered heteroaromatic ring fused with a phenylxe2x80x9d refers to such a xe2x80x9c5-membered heteroaromatic ringxe2x80x9d with a phenyl fused thereto. Representative of such 5-membered heteroaromatic rings fused with a phenyl is benzimidazole.
As used herein the term xe2x80x9cbicycloalkylxe2x80x9d refers to a bicyclic hydrocarbon radical containing 6 to about 12 carbon atoms which is saturated or partially unsaturated.
As used herein the term xe2x80x9cacylxe2x80x9d refers to a radical of the formula 
wherein R26 is alkyl, alkenyl, alkynyl, aryl or aralkyl as defined above. Encompassed by such radical are the groups acetyl, benzoyl and the like.
As used herein the term xe2x80x9cthioxe2x80x9d refers to a radical of the formula 
As used herein the term xe2x80x9csulfonylxe2x80x9d refers to a radical of the formula 
wherein R27 is alkyl, aryl or aralkyl as defined above.
As used herein the term xe2x80x9chaloalkylthioxe2x80x9d refers to a radical of the formula xe2x80x94Sxe2x80x94R28 wherein R28 is haloalkyl as defined above.
As used herein the term xe2x80x9caryloxyxe2x80x9d refers to a radical of the formula 
wherein R29 is aryl as defined above.
As used herein the term xe2x80x9cacylaminoxe2x80x9d refers to a radical of the formula 
wherein R30 is alkyl, aralkyl or aryl as defined above.
As used herein the term xe2x80x9camidoxe2x80x9d refers to a radical of the formula 
wherein R31 is a bond or alkylene as defined above.
As used herein the term xe2x80x9calkylaminoxe2x80x9d refers to a radical of the formula xe2x80x94NHR32 wherein R32 is alkyl as defined above.
As used herein the term xe2x80x9cdialkylaminoxe2x80x9d refers to a radical of the formula xe2x80x94NR33R34 wherein R33 and R34 are the same or different alkyl groups as defined above.
As used herein the term xe2x80x9ctrifluoromethylxe2x80x9d refers to a radical of the formula 
As used herein the term xe2x80x9ctrifluoroalkoxyxe2x80x9d refers to a radical of the formula 
wherein R35 is a bond or an alkylene as defined above.
As used herein the term xe2x80x9calkylaminosulfonylxe2x80x9d refers to a radical of the formula 
wherein R36 is alkyl as defined above.
As used herein the term xe2x80x9calkylsulfonylaminoxe2x80x9d refers to a radical of the formula 
wherein R36 is alkyl as defined above.
As used herein the term xe2x80x9ctrifluoromethylthioxe2x80x9d refers to a radical of the formula 
As used herein the term xe2x80x9ctrifluoromethylsulfonylxe2x80x9d refers to a radical of the formula 
As used herein the term xe2x80x9c4-12 membered mono-nitrogen containing monocyclic or bicyclic ringxe2x80x9d refers to a saturated or partially unsaturated monocyclic or bicyclic ring of 4-12 atoms and more preferably a ring of 4-9 atoms wherein one atom is nitrogen. Such rings may optionally contain additional heteroatoms selected from nitrogen, oxygen or sulfur. Included within this group are morpholine, piperidine, piperazine, thiomorpholine, pyrrolidine, proline, azacycloheptene and the like.
As used herein the term xe2x80x9cbenzylxe2x80x9d refers to the radical 
As used herein the term xe2x80x9cphenethylxe2x80x9d refers to the radical 
As used herein the term xe2x80x9c4-12 membered mono-nitrogen containing sulfur or oxygen containing heterocyclic ringxe2x80x9d refers to a ring consisting of 4 to 12 atoms and more preferably 4 to 9 atoms wherein at least one atom is a nitrogen and at least one atom is oxygen or sulfur. Encompassed within this definition are rings such as thiazoline and the like.
As used herein the term xe2x80x9carylsulfonylxe2x80x9d or xe2x80x9carylsulfonexe2x80x9d refers to a radical of the formula 
wherein R37 is aryl as defined above.
As used herein the terms xe2x80x9calkylsulfoxidexe2x80x9d or xe2x80x9carylsulfoxidexe2x80x9d refer to radicals of the formula 
wherein R38 is, respectively, alkyl or aryl as defined above.
As used herein the term xe2x80x9cphosphonic acid derivativexe2x80x9d refers to a radical of the formula 
wherein R39 and R40 are the same or different H, alkyl, aryl or aralkyl.
As used herein the term xe2x80x9cphosphinic acid derivativesxe2x80x9d refers to a radical of the formula 
wherein R41 is H, alkyl, aryl or aralkyl as defined above.
As used herein the term xe2x80x9carylthioxe2x80x9d refers to a radical of the formula 
wherein R42 is aryl as defined above.
As used herein the term xe2x80x9cmonocyclic heterocycle thioxe2x80x9d refers to a radical of the formula 
wherein R43 is a monocyclic heterocycle radical as defined above.
As used herein the terms xe2x80x9cmonocyclic heterocycle sulfoxidexe2x80x9d and xe2x80x9cmonocyclic heterocycle sulfonexe2x80x9d refer, respectively, to radicals of the formula 
and 
wherein R43 is a monocyclic heterocycle radical as defined above.
The term xe2x80x9ccompositionxe2x80x9d as used herein means a product which results from the mixing or combining of more than one element or ingredient.
The term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d, as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a chemical agent.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
The following is a list of abbreviations and the corresponding meanings as used interchangeably herein:
1H-NMR=proton nuclear magnetic resonance
AcOH=acetic acid
BH3-THF=borane-tetrahydrofuran complex
BOC=tert-butoxycarbonyl
Cat.=catalytic amount
CH2Cl2=dichloromethane
CH3CN=acetonitrile
CH3I=iodomethane
CHN analysis=carbon/hydrogen/nitrogen elemental analysis
CHNCl analysis=carbon/hydrogen/nitrogen/chlorine elemental analysis
CHNS analysis=carbon/hydrogen/nitrogen/sulfur elemental analysis
DCC=1,3-dicyclohexylcarbodiimide
DIEA=diisopropylethylamine
DMA=N,N-dimethylacetamide
DMAC=Dimethylacetamide
DMAP=4-(N,N-dimethylamino)pyridine
DMF=N,N-dimethylformamide
DSC=disuccinyl carbonate
EDCI=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Et2O=diethyl ether
Et3N=triethylamine
EtOAc=ethyl acetate
EtOH=ethanol
FAB MS=fast atom bombardment mass spectroscopy
g=gram(s)
GIHA HCl=meta-guanidino-hippuric acid hydrochloride
GIHA=meta-guanidino-hippuric acid
HPLC=high performance liquid chromatography
IBCF=isobutylchloroformate
K2CO3=potassium carbonate
KOH=potassium hydroxide
LiOH=lithium hydroxide
MCPBA=m-chloroperoxybenzoic acid or m-chloroperbenzoic acid
MeOH=methanol
MesCl=methanesulfonylchloride
mg=milligram
MgSO4=magnesium sulfate
ml=milliliter
mL=milliliter
MS=mass spectroscopy
N2=nitrogen
NaCNBH3=sodium cyanoborohydride
Na2PO4=sodium phosphate
Na2SO4=sodium sulfate
NaHCO3=sodium bicarbonate
NaOH=sodium hydroxide
NH4HCO3=ammonium bicarbonate
NH4+HCO2=ammonium formate
NMM=N-methyl morpholine
NMR=nuclear magnetic resonance
RPHPLC=reverse phase high performance liquid chromatography
RT=room temperature
KSCN=potassium thiocyanate
Pd/C=palladium on carbon
Bn=benzyl
Et=ethyl
Me=methyl
Ph=phenyl
NEt3=triethylamine
t-BOC=tert-butoxycarbonyl
TFA=trifluoroacetic acid
THF=tetrahydrofuran
xcex94=heating the reaction mixture
As used herein HPLC-Method 1 refers to reverse phase C-18 functionalized silica gel column (50xc3x97300 mm) using a linear gradient of 95% 0.6% TFA/water:5% CH3CN to 60% 0.6% TFA/water:40% CH3CN with a flow rate of 80 ml/minute.
The compounds as shown in Formulas I-III can exist in various isomeric forms and all such isomeric forms are meant to be included. Tautomeric forms are also included as well as pharmaceutically acceptable salts of such isomers and tautomers.
In the structures and formulas herein, a bond drawn across a bond of a ring can be to any available atom on the ring.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to a salt prepared by contacting a compound of Formula I with an acid whose anion is generally considered suitable for human consumption. Examples of pharmacologically acceptable salts include the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, tartrate salts and the like. All of the pharmacologically acceptable salts may be prepared by conventional means. (See Berge et al., J Pharm. Sci., 66(1), 1-19 (1977) for additional examples of pharmaceutically acceptable salts.)
For the selective inhibition or antagonism of xcex1vxcex23 integrins, compounds of the present invention may be administered orally, parenterally, or by inhalation spray, or topically in unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes, for example, subcutaneous, intravenous, intramuscular, intrasternal, infusion techniques or intraperitonally.
The compounds of the present invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds required to prevent or arrest the progress of or to treat the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
Accordingly, the present invention provides a method of treating conditions mediated by selectively inhibiting or antagonizing the xcex1vxcex23 cell surface receptor which method comprises administering a therapeutically effective amount of a compound selected from the class of compounds depicted in Formulas I-III, wherein one or more compounds of the Formulas I-III is administered in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as xe2x80x9ccarrierxe2x80x9d materials) and if desired other active ingredients. More specifically, the present invention provides a method for inhibition of the xcex1vxcex23 cell surface receptor. Most preferably the present invention provides a method for inhibiting bone resorption, treating osteoporosis, inhibiting humoral hypercalcemia of malignancy, treating Paget""s disease, inhibiting tumor metastasis, inhibiting neoplasia (solid tumor growth), inhibiting angiogenesis including tumor angiogenesis, treating diabetic retinopathy, inhibiting arthritis, psoriasis and periodontal disease, and inhibiting smooth muscle cell migration including restenosis.
Based upon standard laboratory experimental techniques and procedures well known and appreciated by those skilled in the art, as well as comparisons with compounds of known usefulness, the compounds of Formula I can be used in the treatment of patients suffering from the above pathological conditions. One skilled in the art will recognize that selection of the most appropriate compound of the invention is within the ability of one with ordinary skill in the art and will depend on a variety of factors including assessment of results obtained in standard assay and animal models.
Treatment of a patient afflicted with one of the pathological conditions comprises administering to such a patient an amount of compound of the Formula I which is therapeutically effective in controlling the condition or in prolonging the survivability of the patient beyond that expected in the absence of such treatment. As used herein, the term xe2x80x9cinhibitionxe2x80x9d of the condition refers to slowing, interrupting, arresting or stopping the condition and does not necessarily indicate a total elimination of the condition. It is believed that prolonging the survivability of a patient, beyond being a significant advantageous effect in and of itself, also indicates that the condition is beneficially controlled to some extent.
As stated previously, the compounds of the invention can be used in a variety of biological, prophylactic or therapeutic areas. It is contemplated that these compounds are useful in prevention or treatment of any disease state or condition wherein the xcex1vxcex23 integrin plays a role.
The dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 1000 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions and more preferably of the order from about 0.01 mg to about 100 mg/kg of body weight.
The active ingredient administered by injection is formulated as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier. A suitable daily dose would typically be about 0.01 to 100 mg/kg body weight injected per day in multiple doses depending on the factors listed above and more preferably from about 0.01 to about 10 mg/kg body weight.
For administration to a mammal in need of such treatment, the compounds in a therapeutically effective amount are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and tableted or encapsulated for convenient administration. Alternatively, the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
The pharmaceutical compositions useful in the present invention may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
The general synthetic sequences for preparing the compounds useful in the present invention are outlined in Schemes I-VI. Both an explanation of, and the actual procedures for, the various aspects of the present invention are described where appropriate. The following Schemes and Examples are intended to be merely illustrative of the present invention, and not limiting thereof in either scope or spirit. Those of skill in the art will readily understand that known variations of the conditions and processes described in the Schemes and Examples can be used to perform the process of the present invention.
Unless otherwise indicated all starting materials and equipment employed were commercially available. 
Schemes I-VI are illustrative of methodology useful for preparing various compounds of the present invention. Such methodology is more specifically defined in the examples which follow. Such methodology can be modified by one skilled in the art, substituting known reagents and conditions from conventional methodology to produce the desired compounds.
Scheme I describes a synthesis of a pyridyl xcex2-aminoacid which can be used to synthesize compounds of the present invention wherein R1 is pyridyl. The reaction can be modified using conventional methodology to prepare other aromatic, alkyl or heterocyclic substituted xcex2-amino acids by substitution of the pyridyl carboxaldehyde with any other appropriate aldehyde. Briefly, in Scheme I to pyridinecarboxaldehyde in isopropanol is added ammonium acetate followed by malonic acid. The reaction mixture is stirred at reflux, the resulting precipitate filtered and washed with hot isopropanol and dried to yield 3-amino-3-(3-pyridyl)propionic acid. The ethyl ester is synthesized by heating this acid in excess ethanol in the presence of excess HCl gas.
Additionally, xcex2-amino acids which are useful in the present invention are accessible through modified Knoevenagel reactions (Secor, H. V.; Edwards, W. B. J. J. Org. Chem. 1979, 44, 3136-40; Bellasoued, M.; Arous-Chtar, R.; Gaudemar, M. J.; J. Organometal. Chem. 1982, 231, 185-9), through Reformatski reaction with Schiff bases (Furukawa, M.; Okawara, T.; Noguchi, Y.; Terawaki, Y. Chem. Pharm. Bull. 1978, 26, 260), Michael addition into an acrylic derivative (Davies, S. G.; Ichihara, O. Tetrahedron:Asymmetry 1991, 2, 183-6; Furukawa, M.; Okawara, T R.; Terawaki, Y. Chem. Pharm. Bull., 1977, 25, 1319-25). More recent methods include the use of organometallic reagents in Pd or Zn mediated couplings (Konopelski, J.; Chu, K. S.; Negrete, G. R. J. Org. Chem. 1991, 56, 1355; Mokhallalati, M. K.; Wu, M-J.; Prigden, L. N. Tetrahedron Lett. 1993, 34, 47-50) to complement more traditional reactions such as reductive amination of xcex2-ketoesters.
The racemic beta-alkyl beta amino esters can also conveniently be prepared from the corresponding beta lactam by treatment with anhydrous HCl gas in ethanol. The beta lactams were prepared from the corresponding alkene and chlorosulfonyl isocyanate (Szabo, W. A. Aldrichimica Acta, 1977, 23 and references cited therein). The latter method is useful for the preparation of xcex1 and xcex2-substituted xcex2-aminoacids. (Manhas, M. S.; Wagle, D. R.; Chong, J.; Bose, A. K. Heterocycles, 1988, 27, 1755.) Another route to xcex1-substituted xcex2-aminoacids is the Raney Nickel reduction of cyanoacetic esters at temperatures ranging between 20 and 80xc2x0 C. and at 20 to 100 atm pressure (Testa, E.; Fontanella, L.; Fava, F. Fermaco Ed. Sci., 1958, 13, 152; Testa, E.; Fontanella, L. Annalen 1959, 625, 95). Also, a number of procedures are available for the preparation of xcex2-aminoacids by reduction of hydrazones of keto-acids (Gottijes, J.; Nomte, W. Th. Rec. Trav. Chem. 1953, 72, 721), oximes (Anziegin, A.; Gulewivich, W. Z. Physiol. Chem., 1926, 158, 32) and nitropropionic acids. Purification of final compounds is usually by reverse phase high performance liquid chromatography (RP HPLC) [High Performance Liquid Chromatography Protein and Peptide Chemistry, F. Lottspeich, A. Henscher, K. P. Hupa, (eds.) Walter DeGruyter, New York, 1981] or crystallization. 
Scheme IV represents the synthesis of aminohydrocoumarins (see J. Rico, Tett. Let., 1994, 35, 6599-6602) which are readily opened to form R1 being an orthohydroxyphenyl moiety, further substituted by Z1. 
Specifically, in Scheme V:
In the synthesis of intermediate benzoic acids (A1) through (A16), the starting amino benzoic acids 
are either commercially available or can be converted to such amino benzoic acids via reduction of the corresponding nitro benzoic acid, which can be obtained commercially or syntheized by nitration of the appropriate benzoic acid, followed by reduction to the desired amino benzoic acid. These are all when R5 is H. If R5 is other than H, alkylation of the amino functionality can be achieved by conventional methodology.
Furthermore, synthesis of intermediate (A2) can also be accomplished as disclosed generally in U.S. Pat. No. 3,202,660, starting with the appropriate amino benzoic acid. Furthermore, intermediate (A2) and (A15) as well as further analogues of (A2) and (A15) such as substitutions on the heterocyclic ring, oxazolidines, thiazolidines, benzimidazoles and the like can also be accomplished as disclosed in
1) Chem. Pharm. Bull. 41(1) 117-125 (1993)
2) Chem. Pharm. Bull. 33(10) 4409-4421 (1985)
3) J. Med. Chem. 18 (1), 90-99 (1975). 
xe2x80x83used in the synthesis of intermediates (A3), can be synthesized from 
xe2x80x83and (Me)3OBF4 in dichloromethane. 
xe2x80x83used in the synthesis of intermediate (A4), can be synthesized from Y2xe2x80x94CN and MeOH (1 equivalent) and HCl gas (1 equivalent) in heptane.
All other reagents in Scheme I are either commercially available or readily synthesized by methodologies known by those skilled in the art.
When R50 is not H, the appropriate nitrogen can be alkylated in an appropriate step by methodology known to those skilled in the art. Alternate acid derivatives R are synthesized by methodologies known to those skilled in the art.
To synthesize compounds wherein 
where t=1 and Y3 and Z3 are both hydrogen: 
which is then treated in the same manner of further derivatization as exemplified in the previous schemes for: 
Compounds of the present invention may be prepared as follows:
3-Nitrophenylsulphonylchloride B can be coupled to xcex2-amino acids (as prepared in Schemes I-IV) to afford adduct C. Reduction of C (SnCl2, EtOH, HCl, H2O, 100xc2x0) affords aniline D. Aniline D can be coupled to intermediates (A1-16) as prepared in Scheme V using well known and standard coupling procedures, followed by hydroylosis (or deprotection) of the resulting ester to afford compounds of the present invention.